1-Minute Summary: Eosinophil accumulation in allergic asthma is regulated by the uridine diphosphate–glucose/P2Y14R axis.

Airway hyperresponsiveness (AHR) to allergen exposure induces the production of type 2 cytokines interleukin 5 (IL-5) and IL-3, and the chemokines CCL11/CCL24/CCL26, forming a cytokine/chemokine axis that regulates airway eosinophil accumulation [1]. A recent article demonstrated that this is mediated by the nucleotide sugar UDP-glucose (UDP-G) and the purinergic receptor P2Y14R.

Dr. Tadeucz Karcz et al. (National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA) [2] found that eosinophil migration and accumulation in the lung and AHR are augmented by the nucleotide sugar UDP-glucose (UDP-G) and the purinergic receptor P2Y14R. UDP-G activated P2Y14R on eosinophils to enhance chemokines and promote chemotaxis and activate eosinophil migration to the lung during type 2 inflammation.

The research team showed that P2ry14-deficient mice showed a 50% reduction in eosinophil levels in an allergy-induced experiment, which was not due to decreased expression of chemokines or cytokines. However, experiments with P2Y14R antagonists could not establish an essential or direct role for the P2Y14R pathway on cell activation during allergen sensitisation [1]. The experiments also indicated a requirement of P2Y14R-expressing haematopoietic cells for eosinophil accumulation; when IL-5 and CCL24 stimulate eosinophils, this increased P2ry14-mRNA expression. P2Y14R also has an important role in eosinophil recruitment to the allergic lung and may facilitate amplification of UDP-G, which regulates the distribution of eosinophils in the lungs.

To demonstrate UDP-G involvement in the asthmatic reaction,  mice were sensitised with allergen. This triggered UDP-hexoses release in lung alveolar fluid, which was consequently associated with lung eosinophil accumulation. The authors postulate that eosinophils secrete UDP-G, which further increases eosinophil levels in a positive feedback loop. Overall, the previous studies associated the role of UDP-G and P2Y14R-eosinophil in the allergic lung [1].

Further experiments suggested that P2Y14R was necessary for eosinophils to extravasate, as the eosinophil migration to the lungs was impaired in P2y14-deficient mice. UDP-G in the allergic lung, increased eosinophil infiltration and this was linked with levels of UDP-hexose. In brief, in the allergic lung, the UDP-G/ P2Y14R axis has an important role in amplifying the accumulation of eosinophils [1].

Additionally, genetic analyses of asthma patients identified P2ry14 as a risk gene. No UDP-G level differences between asthmatic and healthy people was found. Only during asthmatic exacerbation, the eosinophil induced UDP-G levels may increase. Moreover, obesity may add to chronic UDP-G/ P2Y14R activation and heightened risk for asthma and its severity.

Pharmacological of genetical inhibition of P2Y14R in eosinophils may possibly decrease eosinophil airway infiltration and AHR. However, the regulation of P2Y14R on eosinophils needs to be further investigated to assess the impact of targeting P2Y14R as treatment for allergic type 2 asthma.  Further research should determine (1) which cytokines are necessary in the mechanism of P2Y14R expression and the recruitment of eosinophils and AHR, (2) other nucleotide sugars and their role in amplifying allergic cell recruitment, and (3) the signaling pathway leading to P2Y14R amplification.

Figure 1: The UDP-G/P2Y14R axis selectively regulates eosinophil migration by promoting chemokines and amplifying chemotaxis.



  1. Foster PS, et al. Elemental signals regulating eosinophil accumulation in the lung. Immunol Rev. 2001;179:173–181.
  2. Karcz, et al. UDP-glucose and P2Y14 receptor amplify allergen induced airway eosinophilia. J Clin Invest. 2021;131(7):e140709.